| First Author | Ayaori M | Year | 2012 |
| Journal | Biochim Biophys Acta | Volume | 1821 |
| Issue | 4 | Pages | 561-72 |
| PubMed ID | 22353356 | Mgi Jnum | J:185065 |
| Mgi Id | MGI:5427300 | Doi | 10.1016/j.bbalip.2012.02.004 |
| Citation | Ayaori M, et al. (2012) Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages. Biochim Biophys Acta 1821(4):561-72 |
| abstractText | ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARalpha/beta/gamma. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARalpha, but not on RARbeta/gamma. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARalpha to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms. |
